Roles of mitochondrial connexin43 in the occurrence of arrhythmias during myocardial ischemia
| Project/Area Number |
19K07298
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 48020:Physiology-related
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| Research Institution | Tohoku University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
佐藤 遥 東北大学, 医学系研究科, 助教 (90803883)
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| Project Period (FY) |
2019-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 不整脈 / コネキシン43 / ミトコンドリア / カルシウム / 細胞内カルシウム |
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| Outline of Research at the Start |
コネキシン43（Cx43）の心筋の虚血/再灌流時における役割は不明である。本研究では心筋虚血時の不整脈発生におけるミトコンドリアCx43の役割の解明を目指す。心筋特異的Cx43欠損マウスを用いて、Cx43の有無が不整脈の発生にどのような影響を与えるのか、その発生に低酸素液潅流とATP感受性K+チャネルがどのような影響を与えるのか、その際にミトコンドリア内カルシウム濃度・膜電位・活性酸素と筋小胞体カルシウム・スパークはどのように変化するのかを記録する。これらの解明は、心筋虚血時の不整脈治療において、ミトコンドリアCx43を標的とした全く新しい発想からの治療法や創薬に繋がる可能性がある。
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| Outline of Final Research Achievements |
Connexin43 (Cx43) exits as hemichannels in the inner mitochondrial membrane. We examined how mitochondrial Cx43 and mitochondrial KATP channels affect the occurrence of triggered arrhythmias. Cardiac-specific Cx43-deficient (cCx43-/-) mice were generated. In cCx43-/- mice, arrhythmias were induced by electrical stimulation at lower [Ca2+]o, and Ca2+ spark frequency, the slope of DCF fluorescence intensity, MitoSoxRed fluorescence, and rhod-2 fluorescence were increased. TMRM fluorescence was decreased in cCx43-/- mice. These changes were suppressed by diazoxide. In cCx43-/- mice, SS-31 and N-acetyl-L-cysteine increased the [Ca2+]o, at which arrhythmias were induced. These results suggest that Cx43 deficiency activates Ca2+ leak from the SR, probably due to an increase in mitochondrial Ca2+ and an increase in ROS production, thereby causing triggered arrhythmias, and that Cx43 hemichannel deficiency may be compensated by activation of mitochondrial KATP channels in mouse hearts.
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| Academic Significance and Societal Importance of the Research Achievements |
不全心や虚血心などにおける細胞内のカルシウム負荷や筋小胞体カルシウム放出チャネルのカルシウム感受性の変化は、カルシウム・スパーク頻度を変化させる。このようなスパーク頻度の変化が、催不整脈性に関与することはよく知られており、催不整脈性における筋小胞体の役割は確立している。一方で、ミトコンドリアの催不整脈性への関与に関しては、ミトコンドリア膜透過性遷移孔の一過性開口やミトコンドリア内カルシウム濃度の上昇がミトコンドリア内ROS産生を増加させ、不整脈を誘発することなどが報告されているものの、依然として詳細は不明である。本研究は、Cx43を標的とした全く新しい発想からの不整脈治療に繋がる可能性がある。
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Report
(5 results)
Research Products
(26 results)
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[Journal Article] Mitochondrial connexin43 and mitochondrial KATP channels modulate triggered arrhythmias in mouse ventricular muscle2023
Author(s)
Sato H,, Nishiyama M, Morita N, Satoh W, Hasegawa T, Someya Y, Okumura T, Koyama S, Shindoh C, Miura M
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Journal Title
Pflugers Arch
Volume: 475
Issue: 4
Pages: 477-488
DOI
Related Report
Peer Reviewed
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[Journal Article] Low-intensity pulsed ultrasound ameliorates cardiac diastolic dysfunction in mice-A possible novel therapy for HFpEF2020
Author(s)
Monma Y, Shindo T, Eguchi K, Kurosawa R, Kagaya Y, Ikumi Y, Ichijo S, Nakata T, Miyata S, Matsumoto A, Sato H, Miura M, Kanai H, Shimokawa H
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Journal Title
Cardiovasc Res
Volume: Jul 19
Issue: 5
Pages: 1325-1338
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Right ventricular longitudinal strain with CMR can more accurately estimate right ventricular functional reserve in rats with pulmonary arterial hypertension2020
Author(s)
Haruka Sato, Yuka Someya, Yui Takahashi, Masami Nishiyama, Ayana Matsumoto, Natsuki Morita, Chiyohiko Shindoh, Hideki Ota, Takuya Ueda, Ryuta Kawashima, Masahito Miura
Organizer
ESC Congress 2020
Related Report
Int'l Joint Research
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